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Analgesics“Opioids” 

Pharmacology

Hiwa K. Saaed PhDPharmacology & Toxicology

College of PharmacyUniversity of Sulaimani

Ref, Lippincott's Illustrated Reviews of Pharmacology 5th ed 2012

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Analgesic

Analgesic – an agent that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness

Pain is: acute or chronicConsequence of complex neurochemical processesSubjective: perceptive and descriptive

Alleviation of pain depend on its type”• Headache, arthritic pain Rx NSAIDs• Neurogenic pain Rx TCA Amitriptyline or SSRI Fluoxetine• Severe or chronic malignant pain Rx Opiods are DOC

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History  /  Definitions

• Ancient Egypt papyrus records reported the use of opium for pain Relief•Opium– mixture of alkaloids from the poppy seed•Opiates naturally occurring alkaloids such as morphine or ‐

codeine obtained from the juice of the opium poppy•Opioid – broad term to describe all “natural or synthetic ”

compounds that work at the opioid receptors and produce morphine-like effects.

endogenous opioid peptide neurotransmittersendorphin, enkephalins & dynorphinsOpiods act by binding to specific opioid receptors in the CNS to produce the

action of endogenous peptide neurotransmitters

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Opioid Classifications

Chemistry• Natural • Semisynthetic • Synthetic

OPIOID RECEPTOR•Mu(μ)•Kappa(κ)•Delta (δ)

INTRINSIC ACTIVITY• agonist,• partial/weak agonist, • antagonist• Mixed agonist/antagonist

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Opioid receptors Mu(μ), Kappa(κ), Delta (δ)

Opioids interact with receptors on the membranes of certain cells in the CNS, on nerve terminals in the periphery on cells of the gastrointestinal tract and the anatomic regions urinary bladder. Analgesic properties are mediated:

•mainly via μ receptors • and κ receptors of the dorsal horn of the spinal cord. • Enkephalins interact more selectively with the δ receptors

in the periphery.

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Endogenous opioid receptorsMuAnalgesia (supraspinal)MiosisRespiratory depressionEuphoriaPhysical dependenceDecrease GIT motility

KappaSpinal analgesiaSedationmiosis

Deltaanalgesia (spinal & supraspinal) release of growth hormoneAffective behaviorPresent in limbic system

Sigma#DysphoraHallucination (both visual & auditory)Respiratory and vasomotor stimulationmydriasis #“less specific” bind with non opioid agent e.g hallucinogen

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Mechanism  of  Action

All are G-protein coupled receptors and inhibit adenylate cyclase. They are also involved in •postsynaptic hyperpolarization

(increasing K+ efflux)•or reducing presynaptic Ca++ influx; thus inhibits neuronal activity.

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Receptor distribution

High densities of opioid receptors on peripheral nerve fibers, immune cells and five general areas of the CNS:

1. Brainstem: respiration, cough, nausea & vomiting, BP, papillary diameter and stomach secretion.

2. Medial thalamus: mediating poorly localized deep pain 3. Spinal cord: in the substantia gelatinosa are involved in

the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli.

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Receptor distribution

4. Hypothalamus: neuroendocrine secretion.5. Limbic system: the greatest concentration in the

amygdale, a major role in emotional behavior & response and little analgesic effect.

6. Periphery: they inhibit Ca+2 dependent release of excitatory, pro-inflammatory substances (substance P)

7. Immune cells: undetermined.

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OpioidsStrong• Alfentanil• Fentanyl• Heroin•Meperidine•Methadone•Morphine• Oxycodone• Remifentanil• Sufentanil

Moderate/low• Codeine• Propoxyphene

• Other• Tramadol

Mixed ag/antag & partial ag• Buprenorphine• Butorphanol• Nalbuphine• PentazocineAntagonists• Nalmefene• Naloxone• naltrexone

Opioid Agonists

• The strongest naturally occurring analgesic drugs are found in opium from the poppy flower,• morphine and less potent codeine. • These drugs show a high affinity for the μ receptor and less

affinity for the κ and δ receptors.

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Morphine

• Exert its effects through interaction with central & peripheral opioid receptors, binding results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release • Acts at the κ receptors in lamina I & II of the substantia gelatinosa

of the cord and decreases the release of substance P, • it also inhibits the release of excitatory transmitters from

nociceptive nerve terminals centrally and in the cord

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Morphine‐Pharmacological  Actions-  Analgesia: Opioids cause pain relief by both • raising the pain threshold at the spinal cord level • altering the central perception of pain; awareness of pain

remains but it loses its unpleasant characterEuphoria: • Opioids produce a sense of contentment and well being, this

may be related to stimulation of the ventral tegmental tractRespiration: • Opioids cause respiratory depression by decreasing the

sensitivity of central respiratory neurons to CO2• Occurs at therapeutic doses and as dose increases respiratory

arrest will occur

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Morphine‐Pharmacological Actions-

Suppression of cough reflex: • Antitussive properties do not correlate with analgesic or respiratory

depression effects; this appears mediated via a different receptor complex

Miosis:• Results from stimulation of μ and κ receptors located in the Edinger‐

Westphal nucleus of CN III, • resistant to tolerance,

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Morphine‐ Pharmacological  Actions-

Emesis:• Opioids directly stimulate the chemoreceptor trigger zone in the area

postrema that causes vomitingGI tract:• Opioids relieve diarrhea by decreasing gut motility and increasing the

tone of intestinal smooth muscle• Constipation is also resistant to tolerance• Biliary spasm is exacerbated by increasing biliary tone with sphincter of

Oddi spasmCardiovascular:• At large doses morphine produces hypotension & bradycardia

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Morphine‐Pharmacological  Actions-

Histamine release:• Morphine causes mast cell degranulation, the release of histamine

causing urticaria, itching, diaphoresis and vasodilation• In asthmatics it may precipitate bronchospasmHormonal Actions:o• inhibits the release of GnRH, CRH • and deceases the release of LH, FSH & ACTH and β endorphin‐• Decrease levels f Testosterone and cortisol• Increase Prolactin and GH release via suppression of dopamine levels

centrally• Increase ADH release

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Morphine‐ Therapeutic  Uses  ‐

• Analgesia:• Few drugs are as effective as morphine for the relief of pain

• Treatment of Diarrhea• Anti tussive:‐

• codeine and dextromethorphanare congeners with greater antitussive effects

• Acute Pulmonary Edema:• – IV morphine dramatically relieves the dyspnea associated with pulmonary

edema due to LV failure

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Morphine‐ Pharmacokinetics  ‐

• Administration:• Morphine is poorly absorbed orally; codeine is a much more effective oral

analgesic• Both undergo extensive first pass metabolism in the liver. Inhalation is an effective

route but has found favor only with non medicinal administration‐• Implantable morphine pumps are also now use for chronic pain

• Distribution:• Morphine readily enters all body tissues except the brain; morphine is the least

lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS much more quickly)

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Morphine‐ Pharmacokinetics  ‐

• Metabolism:• Conjugated in the liver, • morphine–6 glucuronide is a much more potent analgesic; ‐• however morphine 3 glucuronide is less analgesic‐ ‐• Both are excreted in the urine • with small amounts excreted in the bile• Hepatic & renal dysfunction both prolong the normal 4 6 hour duration of action ‐

when administered systemically to morphine-naive individuals • but considerably longer when injected epidurally, because its low lipophilicity

prevents redistribution from the epidural space.

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Morphine‐ Pharmacokinetics  ‐

• Note: A patient's age can influence the response to morphine. • Elderly patients are more sensitive to the analgesic effects of the

drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses. • Neonates should not receive morphine because of their low

conjugating capacity.

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Morphine‐ Adverse  Effects  ‐

• Severe respiratory depression (μ, δ and κ receptors)• Constipation (variable, μ and κ receptors)• Nausea and vomiting• Pupillary constriction (μ/κ receptors)• Caution must be exercised when opiates are used in those with liver

or renal failure • Allergy enhanced hypotensive effects• Elevation of intracranial pressure particularly head injury• Enhance cerebral and spinal ischemia

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Morphine‐ Adverse  Effects  ‐

• In BPH, morphine cause acute urinary retension• Patients with adrenal insufficiency or myxedema may experience

extended and increased effects from the opioids. Morphine should be used with cautiously in patients with bronchial asthma or liver failure.• Note: Many of the effects above can be inhibited by opioid receptor

antagonists such as naloxone.• Rapid development of tolerance• Physical dependence and abstinence syndrome

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Morphine‐Tolerance  &  Physical 

Dependence‐• Repeated use produces tolerance to the effects of respiratory

depression, analgesia, euphoria and sedation• Tolerance does not develop to miosis and constipation • Physical & psychological dependence readily occurs• Withdrawal induces a syndrome associated with autonomic, motor

and psychological responses that are incapacitating, rarely are these life threatening

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Opioid withdrawal syndrome

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comparison of the maximum Efficacy  versus Addiction / Abuse Potential  of  Various Opioids

• Detoxification of heroin- or morphine-dependent individuals is usually accomplished through the oral administration of • methadone, • buprenorphine, or • clonidine.

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Drug interactions:

• The depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs. • The analgesia inexplicably enhanced by Low doses of amphetamine

and hydroxyzine.

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Meperidine “Pethidine” (μ,…κ) • A synthetic opioid structurally unrelated to morphine• Mechanism:

• It binds to μ receptors with some binding at κ receptors

• Actions:• Causes respiratory depression similar to morphine, but less urine retention • no significant CV effect when given orally. • IV administration produces a decrease in PVR resulting in increased peripheral

blood flow & HR.• pupillary dilation via an atropine –like effect.

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Meperidine

• Therapeutic uses:• Severe acute pain• Lacks antitussive activity• No anti diarrhea; • Obstetrics; Produces less smooth muscle contraction/ spasm than morphine

• Pharmacokinetics:• Well absorbed form the GI tract; it is most often given IM• Shorter duration of action than morphine (2 4 hours)‐• Demethylated to normeperidine in the liver and excreted in the urineNB. Because of shorter action and different route of metabolism, meperidine is

preferred over morphine during labor

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Meperidine-Adverse effects:

With large repeated doses normeperidine (demethylated meperidine) accumulates causing • anxiety, muscle tremors and convulsions• Causes papillary dilation (vs. miosis with morphine) in large doses• Hyperactive reflexes• Severe hypotension when admin. postop.• +neuroleptics: enhanced depression• +MAOI: severe reactions convulsion & hyperthermia• Cross tolerance with other opioids‐

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Methadone (μ)

• This is a synthetic orally effective opioid that• is equipotent to morphine • but induces less euphoria • has a longer duration of action

• Mechanism of action:• Binds to the μ receptor.

• Actions:• An equipotent analgesic to morphine• Causes miosis, respiratory depression, biliary spasm and constipation just like

morphine.

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Methadone• Therapeutic uses:

• Used for controlled withdrawal from heroin & morphine• Self addictive but the withdrawal syndrome is somewhat milder but more

protracted than with other opioids

• Pharmacokinetics:• Readily absorbed orally, t1/2 24hrs• Highly protein bound so remains in tissues for a prolonged period.• Transformed in the liver and excreted by the urine as mostly inactive metabolites

• Adverse effects:• Similar to morphine particularly the risk of addiction

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Fentanyl

• Chemically related to meperidine but miosis• has 100 times the analgesic potency of morphine; used in anesthesia and

as analgesia postop & during labor • Highly lipophilic: elimination half life is longer than morphine’s as ‐

redistribution occurs• Rapid onset of action and a short duration (15 30 minutes)‐• Can be used IV, epidurally or intrathecally. Transmucosal and transdermal

preparations are available• Metabolized to an inactive metabolite by the cytochrome P4503A4

system. Drug metabolites are eliminated through the urine.

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Fentanyl

• Like morphine fentanyl causes miosis (vs. mydriasis)• Particular risk of the transmucosal or transdermal routes is

respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and the offset is prolonged• Fentanyl is often used during cardiac surgery because of its negligible

effects on myocardial contractility. • Muscular rigidity, primarily of the abdomen and chest wall, is often

observed with fentanyl use in anesthesia.

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Fentanyl derivative

• Adverse effects of fentanyl are similar to those of other µ-receptor agonists. • Because of life-threatening hypoventilation, the fentanyl patch is

contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics. • Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in

their potency and metabolic disposition. • Only Sufentanil is even more potent than fentanyl others are less potent

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Heroin

• Heroin is produced by the diacetylation of morphine which results in a three fold increase in its potency• Acetylation allows it to cross the BBB much more rapidly yielding a more

pronounced euphoria• May be used IV or smoked, both allow for rapid distribution, • heroin is metabolized to morphine• No medical indication for its use in the clinic.

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oxycodone• is a semisynthetic derivative of morphine. • It is orally active and is sometimes formulated with aspirin or

acetaminophen. • It is used to treat moderate to severe pain and has many properties in

common with morphine. • Oxycodone is metabolized to products with lower analgesic activity. • Excretion is via the kidney. • Abuse of the sustained-release preparation (ingestion of crushed tablets)

has been implicated in many deaths. • It is important that the higher-dosage forms of the latter preparation be

used only by patients who are tolerant to opioids.

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Moderate/Weak Agonists• Codeine• Converted to morphine thus:• Much less analgesic than morphine • Less euphoria and has much lower abuse potential and rarely produces

physical dependence• An effective oral analgesic• Does possess significant anti tussive effects at sub analgesic doses‐ ‐• Often formulated with either acetaminophen, aspirin of ibuprofen; care

but be exerted when these are used with over the counter analgesic to avoid overdose with the non opioid agent‐• A synthetic congener of codeine dextromethorphan lacks analgesic

properties is an effective anti tussive available without prescription‐

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Moderate/Weak Agonists• Propoxyphene• Derivative of methadone, • dextro isomer is analgesic, levo isomer is antitussive• Used for mild to moderate pain; its opioid dose equipotency is

about half of codeine (require twice dose)• Often formulated with another over the counter analgesic; ‐ ‐

combination has greater effect than either drug alone• Toxic doses may produce cardio and pulmonary toxicity particularly

when taken in combination with alcohol and/or sedatives in addition to CNS depression• Opioid antagonists can reverse the pulmonary and CNS effects but

not the cardiotoxicity

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Mixed  Agonists‐Antagonists  &  Partial Agonists

• Pentazocine• Buprenorphine• Butorphanol• Nalbuphine

• Drugs that stimulate one receptor but block another• Effects of these drugs depend on previous exposure to opioids• Naïve patients – drugs act as agonists; produce pain relief• Opioid dependent patients – drugs show blocking affects; withdrawal

syndrome occurs

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Pentazocine

• Pentazocine acts as an agonist on k receptors and is a weak antagonist at µ and delta receptors. • Pentazocine promotes analgesia by activating receptors in the spinal cord,

and it is used to relieve moderate pain. • It may be administered either orally or parenterally. • Pentazocine produces less euphoria compared to morphine. • In higher doses, the drug causes respiratory depression and decreases the

activity of the gastrointestinal tract.• High doses increase blood pressure and can cause hallucinations,

nightmares, dysphoria, tachycardia, and dizziness. The latter properties have led to its decreased use.

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Pentazocine• In angina, pentazocine increases the mean aortic pressure and

pulmonary arterial pressure and, thus, increases the work of the heart. • The drug decreases renal plasma flow. • Despite its antagonist action, pentazocine does not antagonize the

respiratory depression of morphine, • but it can precipitate a withdrawal syndrome in a morphine abuser.

Tolerance and dependence develop on repeated use.

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Mixed  Agonists‐Antagonists  &  Partial Agonists

• Buprenorphine• A partial agonist at μ receptors producing morphine like effects in ‐

naïve users but precipitating withdrawal in morphine dependents• Metabolized in the liver and excreted in the urine and bile• May be taken sublingually or parenteral and possess a long duration

of action• Adverse effects respiratory depression not reversible by naloxone,

hypotension and nausea

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Buprenorphine

• Main use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone• Available outside of the specialized clinic allowed to dispense

methadone for opiate withdrawal

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Antagonists

• Bind with high affinity to the μ, κ & δ receptors but fail to activate the receptor• In normal individuals, these agents produce no effect but in those with

opiates present, they induce an acute withdrawal syndrome• Naloxone• Reverses the coma and respiratory depression associated with opioid

overdose• IV administration produces a reversal of respiratory depression within

~30 seconds• Binding affinity is 10X greater at the μ receptor than κ• Relatively short T1/2 (60 100 minutes) so reversal will often abate ‐

requiring repeat administration

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Antagonists

Naltrexone (hepatotoxic)• Similar actions as naloxone but an oral agent with a much longer

duration of action• Single dose able to antagonize the effects of heroin for up to 48 hoursNalmefene• is a parenteral opioid antagonist with actions similar to that of naloxone

and naltrexone. • It can be administered IV, intramuscularly, or subcutaneously. • Its half-life of 8 to10 hours is significantly longer than that of naloxone

and several opioid agonists.